Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
  • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/88—Nitrogen atoms, e.g. allantoin
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
  • C07D277/44—Acylated amino or imino radicals
  • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines

Definitions

• This invention relates to guanidine derivatives which are histamine H-2 antagonists and which inhibit gastric acid secretion.
• the physiologically active compound histamine which occurs naturally within the animal body, is able to combine, in the course of exerting its activity, with certain specific receptors of which there are at least two distinct and separate types.
• the first has been named the H-1 receptor (Ash and Schild, Brit. J. Pharmac., 1966, 27, 427) and the action of histamine at this receptor is blocked (antagonized) by classical "antihistamine” drugs such as mepyramine (pyrilamine).
• the second histamine receptor has been named the H-2 receptor (Black et al., Nature, 1972, 236, 385) and the action of histamine at this receptor is blocked by drugs such as cimetidine.
• histamine H-2 receptor antagonists which are imidazole and thiazole derivatives having a side chain in the 4-position, to the end of which is attached, for example, a urea, thiourea, guanidine or N-cyanoguanidine. It has now been discovered that if an optionally-substituted guanidino radical is inserted in the 2-position of such compounds, there are produced compounds which are potent histamine H-2 receptor antagonists.
• a guanidine derivative of the formula I ##STR2## in which X is a sulphur atom or an NH radical; Y is a direct bond, a methylene radical or a cis- or trans-vinylene radical; m is 0 to 4 and n is 1 to 4; R 1 is a hydrogen or halogen atom or an alkyl radical of 1 to 6 carbon atoms; R 2 is a hydrogen atom, an alkyl radical of 1 to 10 carbon atoms, an alkanoyl radical of 1 to 6 carbon atoms or an aroyl radical of 7 to 11 carbon atoms; A is a 3,4-dioxocyclobuten-1,2-diyl radical or a radical of the formula C ⁇ Z in which Z is an oxygen or sulphur atom or a radical of the formula NCN, NNO 2 , CHNO 2 , NCONH 2 , C(CN) 2 , NCOR 3 , NCO
• halogen as used herein means that recognized group of halogens which have an atomic weight of at most 127 and are chlorine, fluorine, bromine and iodine.
• a particular value for R 1 when it is a halogen atom or an alkyl radical is a bromine atom or a methyl radical.
• R 2 when it is an alkyl, alkanoyl or aroyl radical is a methyl, n-butyl, acetyl, propionyl or benzoyl radical.
• R 3 is a methyl or p-tolyl radical.
• R 4 is a methyl radical.
• a particular value for B when it is an alkoxy or alkylthio radical is a methoxy, ethoxy or methylthio radical.
• R 5 or R 6 when it is an alkyl, alkenyl, cycloalkyl, (primary hydroxy)alkyl, alkoxyalkyl or dialkylaminoalkyl radical is a methyl, ethyl, n-propyl, isopropyl, n-hexyl, allyl, cyclohexyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl or 2-dimethylaminoethyl radical.
• X is a sulphur atom.
• R 1 is a hydrogen atom.
• R 2 is a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms.
• B is a radical of the formula NR 5 R 6 in which R 6 is a hydrogen atom.
• B is an alkoxy radical of 1 to 4 carbon atoms or an alkylthio radical of 1 to 4 carbon atoms.
• A is a 3,4-dioxocyclobuten-1,2-diyl radical or a radical of the formula C ⁇ Z in which Z is an oxygen or sulphur atom or a radical of the formula NCN, NNO 2 or CHNO 2 .
• Y is a direct bond and m is 2 and n is 2.
• B is a radical of the formula NR 5 R 6 in which R 5 is a methyl radical and R 6 is a hydrogen atom.
• a suitable pharmaceutically acceptable acid-addition salt of the guanidine derivative of the invention is, for example, a salt formed with hydrochloric, hydrobromic, phosphoric, sulphuric, acetic, citric or maleic acid.
• R 7 is a displaceable radical
• A is a radical of the formula C ⁇ Z in which Z is a radical of the formula NCONH 2 and B is a radical of the formula NR 5 R 6 , hydrolysis of a compound of the formula I in which R 2 is a hydrogen atom or an alkyl radical, A is a radical of the formula C ⁇ Z in which Z is a radical of the formula NCN and B is a radical of the formula NR 5 R 6 ;
• R 18 is a radical of the formula CN, COR 3 , CO 2 R 3 or SO 2 R 3 ;
• the process of the invention manufactures the compound of the formula I in the form of the free base and an acid-addition salt is required, the compound of the formula I in the free base form is reacted with an acid which affords a pharmaceutically acceptable anion.
• Process (a) described above may be carried out using an excess of B-H, that is using an excess of the amine R 5 R 6 NH, optionally in the presence of a diluent or solvent such as water, methanol, ethanol and pyridine, or using an excess of the alcohol R 13 OH or the thiol R 13 SH in which R 13 is an alkyl radical of 1 to 6 carbon atoms, preferably in the form of a salt such as the sodium salt in the same alcohol or thiol as diluent or solvent.
• R 7 is preferably an alkoxy or alkylthio radical, for example the methoxy, ethoxy or methylthio radical, or an amino radical. The process may be accelerated or completed by the application of heat, for example by boiling the reaction mixture.
• Process (b) described above may be carried out using an excess of the isocyanate or isothiocyanate R 8 N ⁇ C ⁇ D.
• D is a sulphur atom
• the reaction is preferably carried out in a diluent or solvent such as methanol or ethanol.
• a non-alcoholic diluent or solvent must be used.
• Process (c) described above may be carried out using the sodium salt of dicyanimide in a diluent or solvent such as n-butanol.
• the reaction may be accelerated or completed by the application of heat, for example by heating to the boiling point of the reaction mixture.
• Process (d) described above may be carried out using an excess of the compound of the formula IV in a diluent or solvent such as methanol, ethanol or acetonitrile.
• R 7 is preferably an alkoxy or alkylthio radical, for example a methoxy, ethoxy or methylthio radical.
• the reaction may be accelerated or completed by the application of heat, for example by heating to the boiling point of the reaction mixture.
• Process (e) described above may be carried out using a dilute mineral acid, for example dilute hydrochloric acid, in a diluent or solvent such as water.
• the reaction may be accelerated or completed by application of heat, for example by heating to the boiling point of the reaction mixture.
• Process (f) described above may be carried out in an inert diluent or solvent, and in the presence of a base, at or below room temperature.
• the diluent or solvent is preferably pyridine which also acts as the base.
• the reaction is preferably carried out using the acid chloride or the acid anhydride as the acylating agent.
• R 11 or R 12 is preferably an acetyl, propionyl or benzoyl radical.
• the process may be carried out using a dilute base such as sodium hydroxide in a diluent or solvent such as aqueous methanol or aqueous ethanol.
• Process (h) described above may be carried out using a mild aqueous base, for example aqueous sodium carbonate.
• a mild aqueous base for example aqueous sodium carbonate.
• the reaction may be accelerated or completed by the application of heat, for example by heating to 100° C.
• reaction when D is a sulphur atom the reaction is preferably carried out using an alkyl (C 1 to C 4 ) halide, for example methyl iodide in a diluent or solvent such as ethanol.
• alkyl (C 1 to C 4 ) halide for example methyl iodide in a diluent or solvent such as ethanol.
• the reaction may be accelerated or completed by the application of heat.
• the alkylating agent derived from R 15 --H is preferably the corresponding halide such as methyl iodide.
• the displaceable atom is preferably a halogen atom.
• R 7 is preferably a halogen atom or an alkoxy or alkylthio radical containing 1 to 4 carbon atoms.
• R 7 is preferably an alkoxy or alkylthio radical containing 1 to 4 carbon atoms.
• the starting material of the formula III for use in processes (b), (c) or (d) may be prepared by reaction of a compound of the formula XVI: ##STR15## with a bromoketone of the formula XVII: ##STR16## followed by hydrolysis of the phthalimido residue, for example as set out in following Examples 1, 5 or 17.
• the starting material of the formula XVII may be prepared by a Wittig reaction, for example by reaction of a compound of the formula BrCHR 1 CO(CH 2 ) m CH ⁇ P(Ph) 3 with an aldehyde of the formula XVIII: ##STR17## for example as set out in Examples 27 or 29 followed if necessary by isomerization of the double bond.
• the starting material of the formula III in which R 1 is a halogen atom may be prepared by halogenation of the compound of the formula III in which R 1 is a hydrogen atom, for example as set out in Example 24.
• the starting material of the formula II for use in process (a) may be prepared by reaction of a compound of the formula III with a compound of the formula R 7 --A--R 7 , such as dimethyl (cyanoimido)dithiocarbonate, in which R 7 is a displaceable radical such as methoxy or methylthio, for example as set out in following Examples 1, 5, 7, 11, 12, 18, 19, 22, 27 or 29.
• R 7 is a displaceable radical such as methoxy or methylthio, for example as set out in following Examples 1, 5, 7, 11, 12, 18, 19, 22, 27 or 29.
• the starting material of the formula VI for use in process (h) may be obtained by alkylation of the compound of the formula I in which A is a radical of the formula C ⁇ Z in which Z is an oxygen or sulphur atom.
• the starting material of the formula X for use in process (1) may be prepared, for example, by reaction of a compound of the formula XIX: ##STR18## where R 16 is a radical as described above under process (1); with silver nitrate.
• the starting material for making compounds of formula XIV for use in process (p) may be prepared in the same way as for the starting material of the formula III, but using thiourea in place of the compound of the formula XVI.
• One of the processes of the present invention is then performed on the product, for example in processes (b), (c) and (d), the 2-aminothiazole derivative corresponding to the compound of the formula III, to give the compound of the formula XIV.
• the starting material of the formula XIV may be prepared by reaction of cyanamide with an aminoketone of the formula XX: ##STR19## followed by removal of the phthalimido residue and elaboration of the side chain in the product, the 2-aminoimidazole derivative corresponding to the compound of the formula III.
• the residual gum was purified by column chromatography on silica gel using chloroform/methanol/ammonia (s.g. 0.880) 80:20:0.5 v/v/v as eluant.
• the purified product (0.25 g.) was recrystallized from acetonitrile to give 2-guanidino-4-[4-(2-cyano-3-methylguanidino)butyl]thiazole, m.p. 165°-167.5° C.
• the 2-guanidino-4-(4-aminobutyl)thiazole hydrochloride hydrobromide used at starting material may be prepared as follows:
• 2-Guanidino-4-[2-(2-carbamoyl-3-methylguanidino)butyl]thiazole may be prepared by the following process:
• 2-Guanidino-4-[2-(3-methylureido)butyl]thiazole may be prepared by the following process:
• the 2-(2-methylguanidino)-4-(4-phthalimidobutyl)thiazole hydrobromide used as starting material may be prepared as follows:
• 2-Guanidino-4-[2-(2-cyano-3-(2-methoxyethyl)guanidino)butyl]thiazole may be prepared by the following process:
• 2-Guanidino-4-[2-(2-cyano-3-cyclohexylguanidino)butyl]thiazole may be prepared by the following process:
• 2-Guanidino-4-[2-(2-methoxycarbonylguanidino)butyl]thiazole may be prepared by the following process:
• 2-Guanidino-4-[2-(2-toluene-p-sulphonyl-3-methylguanidino)butyl]thiazole may be prepared by the following process:
• a mixture of dimethyl(toluene-p-sulphonylimido)dithiocarbonate (0.90 g.), triethylamine (0.69 g.), 2-guanidino-4-(4-aminobutyl)thiazole hydrochloride hydrobromide (0.95 g.) and ethanol (10 ml.) is allowed to stand at room temperature for three days.
• An ethanolic solution of methylamine (33% w/v; 3 ml.) is added and the mixture allowed to stand at room temperature for three days.
• the mixture is evaporated to dryness and the residue applied to Merck 60 F-254 preparative thin layer chromatography plates and eluted with chloroform/methanol/ammonia (s.g. 0.880) 5:1:0.1 v/v/v.
• the desired product may then be obtained by extraction of the appropriate region of the developed chromatograms with ethanol.
• the 2-guanidino-4-(4-aminobutyl)imidazole used as starting material may be obtained as follows:
• the 2-guanidino-4-(6-aminohexyl)thiazole dihydrochloride used as starting material may be prepared as follows:
• a mixture of amidinothiourea (1.4 g.) and ethanol (75 ml.) was heated to reflux and the suspension filtered to remove undissolved solids.
• the filtrate was reduced in volume to 25 ml. and this hot solution was added to a hot solution of N-(8-bromo-7-oxooctyl)phthalimide (4.2 g.) in ethanol (10 ml.).
• the mixture was heated under reflux for 45 minutes, evaporated to a small volume and allowed to stand at room temperature.
• the starting materials for use in the above process may be obtained as follows:
• Example 1 The second and third parts of Example 1 were then repeated using the appropriate starting materials in place of N-(6-bromo-5-oxohexyl)phthalimide and the compounds in the following Tables II and III were thus obtained:
• the 2-guanidino-4-(4-aminobutyl)-5-bromothiazole used as starting material may be prepared as follows:
• 2-(2-Acetylguanidino)-4-[(2-cyano-3-methylguanidino)butyl]thiazole may be prepared by the following process:
• Acetic anhydride (0.40 g.) is added to a stirred suspension of 2-guanidino-4-[(2-cyano-3-methylguanidino)butyl]thiazole (1.0 g.) in pyridine (6 ml.) at room temperature. After stirring for two hours the mixture is diluted with water (50 ml.), extracted with methylene chloride (3 ⁇ 30 ml.) and the combined extracts washed with water (100 ml.), dried (magnesium sulphate) and evaporated. The residue is applied to Merck 60 F-254 preparative thin layer chromatography plates and eluted with chloroform/methanol/ammonia (s.g. 0.880) 5:1:0.1 v/v/v. The desired product may be obtained by extraction of the appropriate region of the developed chromatograms with ethanol.
• 2-(2-Benzoylguanidino)-4-[(2-cyano-3-methylguanidino)butyl]thiazole may be prepared by the following process:
• the 2-guanidino-4-(3-aminoprop-1-trans-enyl)thiazole used as starting material may be prepared as follows:
• the 2-guanidino-4-(4-phthalimidobut-1-trans-enyl)thiazole hydrochloride used as starting material may be obtained as follows:
• the guanidine derivatives of the invention are a histamine H-2 antagonist, inhibit the secretion of gastric acid in warm-blooded animals and are therefore useful in the treatment of peptic ulcers and other conditions caused or exacerbated by gastric acidity, such as stress ulceration or gastrointestinal bleeding due to trauma.
• the histamine H-2 antagonist activity may be demonstrated on standard tests, for example by the ability of the compound of the formula I to inhibit the histamine-induced positive chronotropic response in the spontaneously beating right atrium of the guinea pig heart or by its ability to inhibit the histamine-induced increase in the level of cyclic AMP (3,5-adenosine monophosphate), in the presence of a phosphodiesterase inhibitor, in a free cell suspension obtained from canine gastric mucosa.
• cyclic AMP 3,5-adenosine monophosphate
• the guinea pig heart atrium test is carried out as follows:
• a guinea pig right atrium is suspended at 1 g. tension (isometric) in a thermostatically controlled (30° C.) tissue bath (25 ml.) containing oxygenated (95% O 2 ; 5% CO 2 ) Krebs-Hanseleit buffer (pH 7.4).
• the tissue is allowed to stabilize over 1 hour during which time it is washed 2-4 times.
• Individual contractions are recorded with a force-displacement transducer through a strain gauge coupler, and instantaneous rates are monitored with a cardiotachometer.
• a control response to 1 micromole histamine in the above described tissue bath is obtained after which the tissue is washed 3 times and allowed to re-equilibrate to basal rate.
• the test compound After re-equilibration for 15 minutes, the test compound is added to the tissue bath at the desired final concentration. Ten minutes after addition of the compound, a fresh histamine (1 micromole) bath solution is again added to the tissue bath containing the test compound. Then the response to histamine in the presence of antagonist is compared to the histamine control response. The result is expressed as a percentage of the histamine control response. Thereafter, the apparent dissociation constant of the H-2 antagonist is determined by standard procedures.
• All the compounds exemplified in this specification are active on the guinea pig heart atrium test at or below a bath concentration of 10 micromoles, and the more active compounds show complete inhibition of response at this concentration.
• the inhibition of the secretion of gastric acid may be demonstrated in standard tests, for example by the ability of the compound of the formula I, when dosed intravenously, intragastrically or orally, to inhibit the secretion of acidic gastric juice in, for example, rats, cats or dogs provided with gastric fistulae and whose gastric secretion is stimulated by the administration of a secretagogue, for example pentagastrin or histamine.
• a secretagogue for example pentagastrin or histamine.
• a female pure bred beagle (9-12 kg.) having a chronic gastric fistula is fasted overnight with water ad lib. During the experiment the dog is lightly restrained in a standing position.
• the fistula is opened and, after ascertaining the absence of secretion over a period of 30 minutes, a continuous intravenous infusion of secretagogue (0.5 micromole/kg./hour of histamine or 2 micrograms/kg./hour pentagastrin) in saline (15 ml./hour) is begun.
• Gastric acid samples are collected every 15 minutes. The volume of each sample is measured and a 1 ml.
• test compound is administered intravenously in saline and gastric acid samples are collected for a further 2-3 hours during which time the infusion of secretagogue continues uninterrupted.
• test compound When studying the test compound by the intragastric route, the absence of secretion over a period of 30 minutes is ascertained and the test compound, contained in 25 ml. of 0.5% w/v hydroxypropyl methylcellulose and 0.1% w/v TWEEN 80 polyoxyethylene(20) sorbitan monooleate in water (TWEEN is a trademark of ICI Americas Inc.), is instilled into the stomach through a fistula dosing plug. One hour later, the fistula is reopened and intravenous infusion of a secretagogue, as described above, is immediately begun. Gastric acid samples are measured as described above and the approach of acid secretion to a plateau is compared to that of a control animal which is dosed intragastrically only with the dosing vehicle.
• TWEEN 80 polyoxyethylene(20) sorbitan monooleate in water
• test compound When studying the test compound by the oral route, it is administered in a gelatin capsule washed down with 15 ml. of water. One hour later, the fistula is opened and intravenous infusion of the secretagogue is immediately begun. Gastric acid samples are measured as above and the approach of acid secretion to a plateau is compared to that of an undosed control animal.
• results obtained in the heart atrium test are predictive of activity in the dog test.
• a pharmaceutical composition which comprises a guanidine derivative of the invention in association with a non-toxic pharmaceutically acceptable diluent or carrier.
• the pharmaceutical composition may, for example, be in a form suitable for oral, rectal, parenteral or topical administration, for which purposes it may be formulated by means known to the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, dispersible powders, suppositories, sterile injectable aqueous or oily solutions or suspensions, gels, creams, ointments or lotions.
• the pharmaceutical composition of the invention for oral, rectal or parenteral administration may also contain, or be co-administered with, one or more known drugs selected from antacids, for example aluminum hydroxide-magnesium hydroxide mixtures; antipepsin compounds, for example pepstatin; other histamine H-2 antagonists, for example cimetidine; ulcer healing agents, for example dihydrocanadensolide, carbenoxolone or bismuth salts; anti-inflammatory agents, for example ibuprofen, indomethacin, naproxen or aspirin; prostaglandins, for example 16,16-dimethyl-prostaglandin E 2 ; classical antihistamines (histamine H-1 antagonists), for example pyrilamine or diphenhydramine; anticholinergic agents, for example atropine or propantheline bromide; anxiolytic agents, for example diazepam, chlordiazepoxid
• the pharmaceutical composition of the invention for topical administration may also contain, in addition to the guanidine derivative, one or more classical antihistamines (histamine H-1 antagonists), for example pyrilamine or diphenhydramine and/or one or more steroidal anti-inflammatory agents, for example fluocinolone or triamcinolone.
• a topical formulation may contain 1-10% w/w of the guanidine derivative of the invention.
• a preferred pharmaceutical composition of the invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 10 mg. and 500 mg. of the guanidine derivative, or one suitable for intravenous, subcutaneous or intramuscular injection, for example a sterile aqueous solution containing between 0.1% and 10% w/w of the guanidine derivative.
• the slugs should then be ground to form granules that will pass through a 14 to 16 mesh screen.
• the granules may then be recompressed into tablets using a suitable compression mold to form tablets, each weighing 280 mg.
• the present guanidine derivatives or compounds can be used to inhibit the secretion of gastric acid when administered in a therapeutically effective amount to a living, warm-blooded animal in need of treatment for peptic ulcers and other conditions caused or exacerbated by gastric acidity.
• the effectiveness and dosage required vary, as is customary in this art, with the species being treated, particular disorder being treated, weight of the animal, and the route of administration.
• the subject compounds can be used in living animals, for example dogs, in need of such treatment at doses from about 0.03 milligram to 30 milligrams per kilogram body weight (for example b 3 mg./kg.) as needed, generally 2 to 4 times a day.
• a more preferred dose, in view of optimum results and low dosage is from about 0.3 milligram to 3 milligrams per kilogram body weight (for example 1 mg./kg.) as needed, generally 2 to 4 times a day.
• each human patient will receive an oral dose of between 15 mg. and 1500 mg. and preferably between 20 mg. and 200 mg. of a guanidine derivative of the present invention (for example, 50 mg. orally for an adult human) or an intravenous, subcutaneous or intramuscular dose of between 1.5 mg. and 150 mg., and preferably between 5 mg. and 20 mg.
• guanidine derivative of the present invention the subject guanidine derivative being administered 2 to 4 times per day.
• the rectal dose will be approximately the same as the oral dose.
• the composition may be administered less frequently when it contains an amount of guanidine derivative which is a multiple of the amount which is effective when given 2-4 times per day.

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  • 1978-04-20 IT IT22558/78A patent/IT1094469B/it active
  • 1978-04-20 DK DK172778A patent/DK172778A/da active IP Right Grant
  • 1978-04-20 SU SU782607390A patent/SU730299A3/ru active
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• 1979
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  • 1979-08-13 US US06/065,802 patent/US4262126A/en not_active Expired - Lifetime
• 1980
  • 1980-07-25 US US06/172,302 patent/US4347370A/en not_active Expired - Lifetime
• 1982
  • 1982-06-16 FR FR8210491A patent/FR2519341A1/fr active Granted
• 1983
  • 1983-11-18 JP JP58216402A patent/JPS59130277A/ja active Granted
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